Project Summary The results of numerous studies have demonstrated that changes in fast glutamatergic tr ansmission in the amygdala play a major role in neural processes involved in the acquisition and extinction of conditioned fear. However, there are converging lines of evidence suggesting that changes in gamma-aminobutyric acid (GABA) may also be involved in these processes. In humans, involvement of GABAergic transmission in the regulation of fear and anxiety is highlighted by the fact that patients suffering from anxiety disorders are commonly treated by the administration of benzodiazepines (BZs), which mediate their actions via GABAA receptors (GABAARs).The amygdala is particularly rich in GABAARs which are known to be involved in the anxiolytic and anxiogenic effects of GABA agonists and antagonists, respectively. At present, there is a void in research designed to investigate how the changes in amygdala GABAergic transmission influences emotional memories and behaviors associated with anxiety and fear. Recently, our lab reported learningrelated changes in GABA-related genes and GABAAR levels in the amygdala after the acquisition and extinction of Pavlovian fear , a commonly used animal model of fear and anxiety disorders. Our findings showed that the acquisition of fear induced a down regulation of genetic markers related to decreased amygdala GABAergic function;whereas the acquisition of fear extinction produced an up regulation of GABAergic markers related to enhanced GABAergic transmission. This research proposal will employ a novel and powerful approach to investigating the role of amygdala GABAergic transmission in fear and behavioral responses to pharmacological agents. Specifically, in Aim 1 of this proposal, we propose to examine the acquisition and extinction of conditioned fear in mice with knocked down expression of 2-GABAARs or GAD67 in the amygdala using a vector-based RNA interference (RNAi) strategy to locally induce loss-of-function. We hypothesize that associated changes in GABAergic function will decrease the level of phasic inhibition, resulting in facilitated acquisition of fear and blunted extinction of fear. In Aim 2 of this proposal, we plan to examine the behavioral effects of BZ administration in mice with knocked down expression of 2-GABAARs or GAD67 in the amygdala. We hypothesize that associated changes in amygdala GABAergic function will result in blunted anxiety-like behavioral effects to BZ.